1ob-methyl-13b-polycarbonalkylgon-4-en-3-ones

ABSTRACT

13-Aklyl-10-methylgon-4-en-3-ones possessing androgenic, anabolic, progestational activity are prepared from the correspondingly substituted 13-alkyl-10-methylgonan-4-ones wherein groups labile to mesylation are protected to permit selective mesylation of subsequently formed 4-hydroxy group, by converting the 4-one to its 3-hydroxy-methylene derivative, hydrolyzing the oximino group, mesylating the 4-hydroxy group, catalytically hydrogenating the unsaturation at the 4-position, and eliminating the 4-mexyloxy group to form the 4-en-3-one conjugated system.

United States Patent Donald P. Strike Philadelphia; David R. Herbst,King of Prussia; l-lerchel [72] Inventors Smith, Wayne, all of Pa.

21 Appl.No. 551,317

[22] Filed May 19,1966

[45] Patented Sept.21,1971

[73] Assignee American Home Products Corporation New York, N.Y.

[54] 10B-MET HYL-13/3-POLYCARBONALKYLGON-l- EN-S-ONES 9 Claims, 2Drawing Figs. 52 us. c|..'. 260/391.4, 260/239.55, 260/239.S7, 260/3973,260/397.5,

[51] Int. Cl C07c 169/20 [50] Field of Search Machine Searched SteroidsPrimary Examiner-Henry A. French Attorneys-John .l. Hagen and VitoVictor Bellino 4-hydroxy group, by converting the 4-one to its3-hydroxymethylene derivative, hydrolyzing the oximino group, mesylatingthe 4-hydroxy group, catalytically hydrogenating the unsaturation at the4-position, and eliminating the 4-mexyloxy group to form the 4-en-3-oneconjugated system.

PATENYED SEPZI an SHEU 2 OF 2 B Y o NN o row? a lllll INVENTORS DONALDP. STRIKE DAVID R. HERBST HERCHEL SMITH A TTORNEY IOB-METHYL-l3fl-POLYCARBONALKYLGON-4-EN-3- ONES This invention relates tocompositions of matter classified in ,the art of chemistry assubstituted gon-4-en-3-ones.

infrared, ultraviolet, and nuclear magnetic resonance spectrographicanalysis, spectral data supporting the molecular structure hereinbeforeset forth. For example, the l-methyl and the l3-polycarbonalkyl groupsare evident in the nuclear magnetic resonance spectrum and the4-en-3-one conjugated system is evident in the ultraviolet and infraredspectra. The aforementioned physical characteristics, taken togetherwith the elemental analysis, the nature of the starting materials, andthe mode of synthesis, further confirm the molecular structurehereinbefore set forth for the compositions sought to be patented.

The tangible embodiments of the principal compositions of the inventionpossess the inherent applied use characteristics of exertingqualitatively varying hormonal effects in animals as evidenced bypharmacological evaluation according to standard test procedures. Suchtangible embodiments possess androgenic, anabolic, progestational, andantiandrogenic activity. in addition to their inherent applied usecharacteristic, the compositions of the invention possess the furtherapplied use characteristic of being intermediates for makingcompositions which possess applied use characteristics of exertingqualitatively varying hormonal effects in animals as evidenced bypharmacological evaluation according to standard test procedures andwhich are within the generic scope of the invcntion.

The invention sought to be patented in a principal process of making thecompositions aspect, is described as residing in the concept ofasequence of reactions, including: converting a l7-hydroxy-lO-methyl-3-alkylgonan-4-one whose 1?- hydroxy group is protected to permitselective mesylation of the hereinafter formed 4-hydroxy group to the3-hydroxymethylene derivative, converting the so-obtained3-hydroxymethylene derivative to the corresponding 3-oximino derivative,hydrolyzing the 3-oximino derivative to obtain the corresponding4-hydroxy-4-en-3-onc; mesylating the 4-hydroxy group, catalyticallyhydrogenating the unsaturation at the 4- position and eliminatingmethane sulfonic acid to obtain a 13- alkyl-lO-methylgon-4-en-3-one.

The invention sought to be patented in a first subgeneric aspect is a4-hydroxyl O-methyl-l3-polycarbonalkylgon-4-en- 3-one.

The tangible embodiments of the primary first subgeneric aspect of theinvention possess the inherent general physical properties of beingwhite crystalline solids, are substantially insoluble in water and aregenerally soluble in polar solvents such as dimethylacetamide.Examination of compounds produced according to the hereinafter-describedprocess reveals, upon ultraviolet, infrared, and nuclear magneticresonance spcctrographic analysis, spectral data confirming themolecular structure hereinbefore set forth. For example, the 4 hydroxy4cn .l-one structure is assigned rather than the theoretical alternative3 hydroxy2-en-4-one, from its proton nuclear magnetic resonance spectrumwhich shows no signal for a vinyl proton. The aforementioned physicalcharacteristics taken together with the elemental analysis, the natureof the starting materials, and the mode of synthesis, further confirmthe structure of the compositions sought to be patented.

The tangible embodiments of said first subgeneric composition aspectpossess the applied use characteristic ofbeing intermediates for thepreparation of compositions exerting hormonal effects as evidenced bystandard test procedures.

The invention sought to be patented in a second subgencrie compositionaspect is described as residing in the concept ofa 4-methylsulfonyloxylO-methyI l 3-polycarbonalkylgon-4-en- 3one.

The tangible embodiments of the second subgeneric com position aspect ofthe invention possess the inherent general physical properties of beingwhite crystalline solids, are sub stantially insoluble in 'water, aregenerally solublein polar solvents, such as dimethylacctamide.Examination of the compounds produced according to the hereinafterdescribed process reveals, upon infrared, ultraviolet, and nuclearmagnetic resonance spectrographic analysis, spectral data confirming themolecular structure hereinbefore set forth. For example, the 4-en-3-oneconjugated system is evident in the ultraviolet. The aforementionedphysical characteristics, taken together with the elemental analysis,the nature of the starting materials, and the mode of synthesis furtherconfirm the structure of the compositions sought to be patented.

The manner of making and using the invention will now be generallydescribed so as to enable a person skilled in the art of chemistry tomake and use the same as follows: in describing the invention, referencewill be made to the annexed drawings, wherein:

FIG. 1 illustrates schematically the reaction sequence for preparing agon-4-en-3-one having attached thereto a methyl group at the lO-positionand an alkyl group at the l3-position from the corresponding gonan4-0ne,specifically l3-ethyl-l 7- hydroxy-lO-methlgon-4-en-3-one froml3-ethyl-l7-hydroxylO-methlgonan-4-one.

FIG. 2 illustrates schematically the reaction sequence for using agon-4-en-3-one having attached thereto a methyl group at the l0-positionand a l3-polycarbonalkyl group, specifically l3-ethyl l7-hydroxy-lO-methylgon-4-en 3-one, as intermediates for making othercompositions possessing the applied use characteristic of exertingqualitatively varying hormonal effects in animals,

Referring now to FIG. 1 wherein the compounds are as signed Romannumerals sequentially for identification, the starting materials for theprocess of the invention i.e. the 13-alkyl-l7-hydroxy-lO-methylgonan-4-one (l) are prepared as described inU.S. Pat. Application, Ser. No. 55l,39l filed even day herewith now U.S.Pat. No. 3,452,004 and in the Preparations appended hereto. Thel7hydroxy group of said starting compound is esterificd preferably withaceticanhydride in the presence of pyridine to protect the labile 1?-hydroxy group so as to permit selective mesylation of the later-formed4-hydroxy group in the hereinafter-described reactions. The l7-hydroxygroup can also be protected by forming other alkanoyl or aroyl esters orby other methods known to those skilled in the art of chemistry. Theso-formed ester (II) is treated with ethyl formate and an alkali metalalcoholate such as sodium methoxide to prepare the corresponding3-hydroxymethylene derivative (lll). Reaction with an alkali metalnitrite such as sodium nitrite in acetic acid-methylene dichlorideconverts the 3-hydroxyrnethylene derivative to the corresponding3-oximino derivative (lV). Hydrolysis of the said oxime produces thecorresponding 4- hydroxy-4-en-3-one (V). Mesylation of the 4-hydroxygroup with methane sulfonylchloride in pyridine tVl), followed byhydrogenation ofthe 4-unsaturation in-the presence of it) percentpalladizcd charcoal (VII), and dehydromesylation by treatment withlithium chloride-lithium carbonate at l4tlin dimethylformamitle yieldsthe corresponding l3-alkyl-l7- hydroxy-l0-methylgon-4-en-3-one ester(Vlll). ()n hydrolysis of the protecting l7-estcr, there is obtainedl3-alkyl-l7- hydroxy-l0-methytlgon-4-en-3one.

Referring now to FIG. 2, wherein the compounds are also assigned Romannumerals sequentially for identification, there is schematicallyillustrated methods of using compounds of the invention by convertingthem to other compounds within the generic scope of the invention, whichpossess the applied use characteristics of exerting qualitativelyvarying hormonal characteristics in animals as evidenced bypharmacological evaluation according to standard test procedures. Byreference to FIG. 2 and the appended examples, or to the chemicalliterature, the procedure for converting the 17- hydroxy group of thecompound produced by the process of the invention in FlG. 1 (IX) or itsesters (Vlll), by methods known in the art, to l7-carbonyl (Xl) (Xll),and converting said carbonyl to alkylhydroxymethylene (XV) (XVl), forexample the l7a-methyl-l7/3-hydroxy or l7B-ethyl-l7a-hydroxy derivativeby addition of the appropriate organometallic compound, or toalkynylhydroxymethylene (Xlll) (XIV) for example thel7a-ethynyl-l7B-hydroxy, r l7a-chl0r0ethynyll7B-hydroxy derivative byaddition of the appropriate alkali metal acetylide, toalkenylhydroxymethylene, for example the l7a-alkenyl-l7fi-hydroxyderivative by reduction of the alkynylhydroxymethylene, or toprogesterone (Xlll XXl) and desoxycorticosterone acetate XXlll)homologs, is evident. The l7-carbonyl group may also be ketalized orthioketalized by treating with the appropriate alcohol or glycol, in asuitable solvent under acidic conditions, as in the presence of an acidsuch as sulfuric acid, p-toluenesulfonic acid, or boron trifluorideetherate, with heating where necessary according to known procedures.Similarly the l7-hydroxy can be converted to carboxylic acid estersother than the acetate, including esters of aliphatic and aromaticacids, or it can be etherified to form l7-ethers by procedures known inthe art.

The hereinbefore described processes of making and using offer a novel,unique, and feasible wholly synthetic route to the corresponding naturalsteroids if the l3-alkyl group in the starting compound is methyl, forexample testosterone, progesterone and the corticoids. Moreover asindicated above they offer a novel, unique, and feasible totallysynthetic route to compounds unobtainable from natural steroids, whenthe l3-alkyl group is polycarbonalkyl. The l3-polycarbonalkyl group canbe of varying chain length, such as, for example, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, etc., even cetyl, and for theprocesses of the invention when such groups are present in the startingmaterial, they will correspondingly be present in the intermediates andthe final product, and are full equivalents in the process asparticularly described and claimed.

It will be apparent to those skilled in the art that the startingcompounds can bear groups which are unaffected by the process reactionssuch as, for example, but not limited thereto, 6- or 7-methyl, or thestarting compound can bear other labile groups which can be protected toallow selective reaction, such as, for example, but not limited thereto,the l 1- hydroxy or the 16-hydroxy group which can be protected byesterification in analogous fashion to the manner in which thel7-hydroxy group is protected in the description hereinabove, and thesevariations for the process of the invention, except for the limitationsexpressed above, are full equivalents 'of the process, as particularlydescribed.

It will also be apparent to one skilled in the art of chemistry that ifthe l7-position of the starting material is substituted only withhydrogen, or with a group inert to the subsequent process reactions,that protection of the l7-position to permit selective reaction is notrequired, and that when a starting material thus substituted is employedin the process of the invention, this variation is the full equivalentof the process as particularly described and claimed.

While the tetracyclic compounds in the specification and the appendedexamples are named either without regard to configuration or to describethe configuration corresponding to that of the natural steroid, it is tobe understood, the product of the given manipulative procedures is aracemic mixture which contains the compound corresponding to the naturalsteroid and its enantiomorph if the starting compound was a racemicmixture. However, if the starting compound is a particular enantiomorphthe final product also has the same enantiomorphic configuration.

When employed in the applied use characteristic of exertingqualitatively varying hormonal effects, the products of the inventionare administered in pharmaceutical forms known to those skilled in theart of pharmacy. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories. A solidcarrier can be one or more substances which may also act as diluents,flavoring agents, solubilizers, lubricants, suspending agents, binders,or tablet disintegrating agents; it can also be an encapsulatingmaterial. In powders the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablets thecompoundis mixed with a carrier having the necessary binding propertiesin suitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain from 5 to 10 to 99 percent of theactive in gredient. Suitable solid carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tracanth, methyl cellulose, sodium carboxymethylcellulose,low-melting wax, and cocoa butter. Tablets, powders, cachets, andcapsules can be used for oral administration, and can be incorporatedinto formulations to obtain delayed or sustained release effects.

Liquid form preparations include solutions, suspensions, and emulsions.The compounds are insoluble in water, but can be dissolved inaqueous-organic solvent mixtures that are nontoxic in the amounts used.As an example may be mentioned waterpropylene glycol solutions forparenteral injection. Liquid preparations can also be formulated insolution, in aqueous polyethyleneglycol. Aqueous suspensions suitablefor oral use can be made by dispersing the finely divided compound inwater with viscous material, such as natural or synthetic gums, resins,etc., for example, gum arabie, ionexchange resins, methylccllulosc,sodium carboxymcthylccllulose, and other known suspending agents.

The quality of compound in a unit dosage form may be adjusted from lessthan 1 mg. to 100 mg. (generally within the range of 2.5 to 25 mg. andthe effective dosage depends upon the severity of the condition beingtreated, the stage, the individual case, and the compound, and will bedetermined by an attending physician. Generally, a dosage range of from0.25 to about 15 mg. per kg. of body weight per day constitutes theoverall range.

The following examples illustrate the best mode contemplated by theinventors of carrying out the process of the invention and the manner ofmaking and using as intermediates the compositions of the invention.PREPARATlON l di-l3-Ethylogon-4-en-173-0], acetate C H O, analysis:

Calculated Found C,79.70;H, 101%. C,79,69; H, 10.31%.

Prepare in an analogous manner, the l3-methyl compoundd-estr-4-cn-l7B-ol, acetate, m.p. 8l-82, k211i; 5.80, 8.00 IJ. fromd-estr-4-en-l 7Bol.

PREPARATION 2 dl 5g-bromo-l 3,8-ethyll 7B-hydroxygonan-4-one, acetateTreat a solution of 4.7 g. of dl-13 B-ethylgon-4en-l7B-ol, acetate in100 ml. of dioxane and 25 mlv of water with 3.4 g. of N-bromosuccinimideand a solution of 1.0 ml. of 70 percent perchloric acid in 5 ml. ofwater. Keep the mixture at room temperature for 1.25 hours, decolorizethe orange solution with potassium bicarbonate dilute with 200 ml. ofwater and extract four times with ether. Wash the ether extract withwater, dry over sodium sulfate and evaporate to obtain 6.56 g. of crudebromohydrin, an oily solid.

Treat a stirred, cooled solution of the above bromohydrin (6.56 g.) in100 ml. of acetone with Jones reagent (8N chromium trioxide in aqueoussulfuric acid) until an orange color persists Remove the cold water bathand stir the solution for 20 minutes. Destroy the excess Jones'reagentwith isopropyl alcohol, neutralize the solution with potassiumbicarbonate, evaporate to a slurry, dilute with water and extract fourtimes with ether. Wash the ether extract with water, dry over sodiumsulfate and evaporate to yield 5.54 g. of a yellow, oily solid.Crystallize from acetone-hexane to obtain the max max.

title product, m.p. l37138, 5.77, 5.84, 8.01 11.,

Analysis for C,,H BrO,-,:

Calculated C, 6131,11, 7.60; Br, 19.42%. Found C, 61.45; H, 7.37; Br,19.0%.

Prepare in an analogous manner, the 13Methyl compound, d-Sf-bromol 7B-hydroxyestran-4-one, acetate, m.p. l5l-153 Affififf 5.75, 5.87, 8.00p. from d-estr-4-en-17B-ol,

acetate.

PREPARATION 3 d1 1 3B-ethyll 7,B-hydroxygon-5( 10)-en-4one, acetatep.p.m.

Analysis for C,,H,,,o,;

Calculated C, 76.32; H, 9.15%. Found C, 76.08; H, 9.01%.

Prepare in an analogous manner, the l3-methyl compound,d-l7B-hydroxyestr-5(10)-en-4-one, acetatd fitp." l40. 5 142, My}; 5.75,6.05, 6.17, 8.05 1., A2 3; 251 mp. (5 13 ,000), from d-Sg-bromo- 17Bhydroxyestran-4-one, acetate.

PREPARATION 4 Add a solution of 2.7 ml. of hydrocyanic acid in 50 ml. ofcooled tetrahydrofuran slowly to a stirring ice cold mixture of 82.0 ml.of 25% diethyl aluminum bromide in heptane and 80 ml. of tetrahydrofuranunder nitrogen. Add a solution of 7.9 g. ofdl-l3B-ethyl-l7fi-hydroxygon-5( l)-en-4-one, acetate in 75 ml. oftetrahydrofuran to the above mixture, remove the ice bath, discontinuethe nitrogen and stopper the flask lightly. Keep the mixture at roomtemperature for 5 hours, and then add slowly to 1 liter of stirring icecold 5% sodium hydroxide and extract with chloroform. Wash the extractwith water, dry over sodium sulfate and evaporate to obtain 8.82 g. ofpale yellow solid. Run a benzene solution of the crude product through ashort neutral alumina (activity 3) column and crystallize the resultingsolid from hexane-acetone to obtain the title product, m.p. 183-185", A4.50, 5.80, 8.00 p

max

Analysis for CnH,NO,:

Calculated C, 73.91; H. 8.74, N, 3.92%. Found C, 74.08; H, 8.43; N,3.88%.

Prepare in an 22 manner, the l3methyl compound, d-lOB-cyano-l7B-hydroxy-5a-estran-4-one, acetate, m.p. 201-203", x3533; 4.50,5.80, 8.01 p, from d-17B-hydroxyestr-5( )-en-4- one, acetate.

PREPARATION 5 dl-l3/3-Ethyl-17B-hydroxy-l0/3-methyl-5/3-gonan-4-onechloroform. Wash the extract with water, dry and evaporate to obtain 6.0g. of white, solid ketal.

Add a solution of .the above 6.0 g. of ketal in 200 ml. oftetrahydrofuran dropwise, over 15 minutes, to a stirring ice coldmixture of 6.0 g. of lithium aluminum hydride in 400 m1. oftetrahydrofuran under nitrogen. Reflux the mixture for 18 hours, cool.in ice and decompose cautiously by adding a mixture of ml. of,0.86 Mpotassium sodium tartrate and 25 ml. of 0.5 M tartaric acid. Dilute themixture with water and extract with chloroform. Wash the extract withwater, dry and evaporate to obtain 6.0 g. of white imine.

Stir and heat a solution of the above 6.0 g. of imine, 30 g. of

.potassium hydroxide and 30 ml. of hydrazine hydrate in 420 ml. ofdiethyleneglycol at a reaction temperature of for 2 hours, Remove thecondenser, heat the reaction until the temperature attains 210, replacethe condenser and reflux the mixture for 6 hours. Dilute the cooledsolution with water, extract with chloroform and wash the extract withwater, dry and evaporate to obtain 4.3 g. of solid methyl-ketal.

Reflux a solution of the above 4.3 g. of methyl-ketal in 200 ml. ofacetone and 10 ml. of concentrated hydrochloric acid for 15 minutes,evaporate and dilute with water. Extract the mixture with chloroform andwash with water, dry, evaporate and chromatograph on neutral alumina(Act. 3). Elute with benzene and recrystallize from acetone-hexane toobtain the title product, m.p. l82-184, A233,: 2.90, 5.92 ,t. NMR: 0.75,1.88, 3.74 (triplet) p.p.m.

Analysis for C H o t Calculated C. 78.89; H. 10.59%. Found C. 78.75; H.10.47%.

Prepare in an analogous manner, the l3-methyl compoundd-l7/3-hydroxy-5pl-androstan-4-one (reported in Helv. Chim. Acta 46,352-64 (1963) and CA 58, l405lg.) from d-lOB-cyano-l7fl-hydroxy5a-estran-4-one, acetate.

EXAMPLE 1 d- 1 7fl-Acetoxy-5a-androstan-4-one Heat d-l7B-hydroxy-5a-androstan-4-one (0.97 g.) on a steam bath for one hourin acetic anhydride (5 ml.)pyridine (15 ml.) to obtain the title productas a yellow solid.

EXAMPLE 2 dll 7B-Acetoxy- 1 3B-ethyl-b 10Bmethylgonan-4-one Treatdl-lBB-ethyl-l7B-hydroxy-10B-methylgonan-4-one by the method of example1 to obtain the title product m.p. l74-l76 )rffifl'; 5.74, 5.84, 8.1014.

EXAMPLE 3 d- 1 7B-Acetoxy-3-hydroxymethylene-5aandrostan-4-one Keep theproduct of example 1 (1.1 g.) for 2 days in ether (50 ml.)-ethyl formate(10 ml.) containing sodium methoxide (2 g.). Add water, separate theaqueous layer and wash it with ether, acidify with hydrochloric acid,and extract with chloroform. Wash the chloroform solution with water,dry and evaporate to obtain the title product (0.96 g.), )t,,, ,279 mu.

EXAMPLE 4 d1-17,8Acetoxy-13B-ethyl-3-hydroxymethylene-10B-methylgonan-4-one Treat the product of example 2 by the method ofexample 3 to obtain the title product, A 281 mu.

EXAMPLE 5 dl 7B-Acetyoxy-3-oximino-5a-androstan-4-one EXAMPLE 6dl-l7B-Acetoxy-l3B-ethyl-10/3-methyl-3l-oximinogonan-4- one Treat theproduct of example 4 by the method of example 5 to obtain the titleproduct, A523? 235 mu.

EXAMPLE 7 d-4-Hydroxytestosterone-l 7-acetate 6.1, and 8.05 t. NMR:0.83, 1.17, 2.04, 4.64 (triplet) 2.84

p.p.m.

Analysis for C,,H,.,O,:

Calculated C, 72.80; H, 8.73%. Found C,73.28;H,8.37%.

EXAMPLE 8 (11-1 3fi-Ethyl-4,l7B-dihydroxy-l0B-methylgon-4-en3-one, l7-acetate 'l'rcut the product ol'exnmple 6 by the method of example 7 toobtain the title product, m.p. 184186, )\l,,,',,{; 2.95, 5.75, 6.0,6.10, 8.05 ,u., 275 my. (12,600). NMR: 1.17, 2.03, 3.87 (triplet), 6.18p.p.m.

Analysis (or C,,H,,O,:

Calculated C, 73.30; H, 8.95%. Found C, 73.22; H, 8.89%.

EXAMPLE 9 d-4,17B-Dihydroxyandrost-4-en-3-one,

17-acetate, 4-methanesulfonate Keep d-4,17B-dihydroxyandrost-4-en-3-one,17-acetate (5 g.) at 0 with methanesulfonyl chloride (5 ml.) in pyridine(100 ml.) for 16 hours. Add the mixture to ice water (1 l.) and filterthe precipitate. Treat the precipitate with Norit in acetone andrecrystallize from acetone-hexane to obtain the title product (4.2 g.),m.p. l187, A 248 mp.

(14,900; 5.78, 5.93, 6.20, 7.40, 8.03, and 8.59 us,

max.

NMR: 0.83, 1.26, 2.03, 3.37, 4.65 (triplet) p.p.m.

Analysis for C H O S:

Calculated C, 62.24; H, 7.60; S, 7.6%.

C, 62.53; H, 7.47; S, 7.7%. acetonehexane, treat with Norit in acetoneFound and recrystallize from acetonehexane EXAMPLE 10 dl-l3B-ethyl-4,17B-dihydroxy-10B-methylgon-4-en-3-one.

17-acetate, 4-methan'esulfonate max.

1.26, 2.04, 3.37, 4.67 (triplet) p.p.m.

Analysis for C H O S:

Calculated C, 62.93, H,7.81;S,7.31%.

Found C, 63.01; H, 7.88; S, 7.2%.

EXAMPLE 1 l d-4- l 7B-dihydroxy-5 -androstan-3-one,

17-acetate, 4-methanesulfonate Shake the product of example 9 (1.0 g.)at atmospheric pressure under hydrogen in ethyl acetate (40ml.)-sulfuric acid (1 ml.) containing 10% palladized charcoal (0.2 g.).After 1.4 moles of gas have been absorbed (35 min.), filter the mixtureand wash the filtrate successively with 5% aqueous Kl-lCO and water, dryand evaporate. Dissolve the residual solid in acetone (60 m1.) and add 8N chromic acid in aqueous sulfuric acid (A. Bowers, T. G. Halsall, E. R.H. Jones, and A. J. Lemin, J. Chem. Soc. 1953, 2555) dropwise withstirring until a red color persists. Stir for a further 30 min.,discharge the red color with isopropyl alcohol, concentrate the mixtureto 15 ml., dilute with water, and extract with chloroform. Evaporate thewashed and dried extracts and crystallize the residue fromacetone-n-hexane to obtain the title product (0.55 g.). The analyticalsample has m.p. 174l75 (decomposition), 5.74, 7.40, 8.05 and 8.53 .1..

max.

Analysis for C H O S:

Calculated C, 61.9; H, 8.0; S, 7.5%.

Found C, 62.0;1-1, 8.0; S, 7.8%.

EXAMPLE 12 dl-l 3 B-ethy1-4, l7B-dihydroxy-l0fl-methyl-5-gonan-3-one,

l7-acetate-4-methanesulfonate Treat the product of Example 10 by themanipulative procedure of example 11 to obtain the title-product, m.p.l87-188(Dec.); X 5.80, 8.0, 8.50 1..

max.

Analysis for C H O S:

Calculated C, 62.70; H, 8.24; S, 7.28%. Found C, 62.82; H, 8.27; S,7.3%.

EXAMPLE l3 d-Testosterone acetate Stir and heat the product of example11 (0.54 g.) undernitrogen for 4 hours with lithium chloride (2 g.) andlithium carbonate (1.2 g.) in dimethylformamide (75 ml.) at 140.

Evaporate the solvent and percolate the residue in benzene through ashort column of a alumina (activity 3). Crystallize.

the product from acetone-hexane, treat with Norit in acetone andrecrystallize from acetone-hexane to give the titleproduct; m.p.137-139", undepressed on admixture withauthentic testosterone acetateand having an identical NMR spectrum, A218? 6.20 and 8.0 u.

241 my. (16,000), x22; 5.75, Calculated Analysis for C H O Calculated C,76.3; H, 9.15%. Found C, 76.2; H, 9.2%.

EXAMPLE 14 dll 3,8-Ethyll 7B-hydroxyl B-methygon-4-en-3-one,

l 7-acetate Treat the product of example 12 by the manipulativeprocedure of example 13 to obtain the title product, m.p. 159l60 AER;5.75, 5.98, 6.20, 8.1011,, A522, 238 m,u( 15,700), NMR: l.l8,2.02, 4.67(triplet), 5.72 p.p.m.

Analysis 1'01 C H O Calculated C, 76.70; H, 9.36%.

Found C, 76.75; H, 9.08%.

methylgon-4-en-3-one, acetate, 2.0 g. of potassium hydroxide,.

ml. of water and 100 ml. of methanol under nitrogen for 1 hour.Concentrate the mixture to a slurry, dilute with chloroform, wash withwater and dry over sodium sulfate.

Evaporate the chloroform solution and crystallize the residue fromacetone to obtain 1.0 g. of the title product, m.p. 198-200 mg; 3.0,6.00, 6.20 u, APE 240 mp. (515,600), NMR: 1.03 (triplet), 1.20, 1.90,3.75 (triplet), 5.74 p.p.m.

Anulysis for C, H,,,O,:

Calculated C, 79.42; H, 10.00%.

Found C, 79.23; H. 9.93%.

EXAMPLE l6 dll 3fl-Ethyl-3 ,3-ethylenedioxy- 1 OB-methylgon-S-enl 7-oneReflux a mixture of 0.35 g. ofdl-l3B-ethyl-17B-hydroxyl0fi-methylgon-4-en3-one, 20 mg. ofp-toluenesulfonic acid, 4 ml. of ethylene glycol and 40 ml. of benzenewith a Dean- Stark water separator for 18 hours. Dilute the mixture withether, wash with water, dry and evaporate to obtain 0.50 g. ofdl-l3fi-ethyl-3,3-ethylenedioxy-1OB-methylgon-S-en-17/3-01.

Reflux the above 0.50 g. of 3-ketal in ml. of benzene and 25 ml. ofmethyl ethyl ketone under nitrogen for one-half hour with a Dean-Starkwater separator after removing the first 20 ml. of benzene distillate.Add asolution of 0.5 g. of aluminum isopropoxide in 15 ml. of benzeneand reflux the mixture under nitrogen for 4 hours. Dilute the mixturewith ether, wash with water, dry and evaporate. Chromatograph theresulting residue on neutral alumina (Act. 3) and elute with benzene toobtain 0.26 g. of the title product, m.p. 162-166", k 5.75 ,u.. 1

EXAMPLE 17 dl-13B-Ethyl-3 ,3-ethylenedioxy-17a-ethynyl-17B-hydroxy-IOB-methylgon-S-ene Bubble acetylene through a stirred solution of 1.0g. of d1- 13/3-ethy1-3,3-ethylenedioxyl OBmethylgon-S-enl7-one in 35 ml.of dimethyl acetamide at room temperature for threequarters hour. Add0.7 g. of lithium acetylideethylenediamine complex and stir at roomtemperature for 2% hours. Add the solution slowly to ice water mixtureand extract with ether. Wash the ether extract with water, dry andevaporate to obtain 1.0 g. of the title product, a solid whose infraredspectrum is devoid of ketone absorption.

EXAMPLE l8 d1-l3,8-Ethyl-17a-ethynyl-l7/3-hydroxy-10B-methylgon-4-en-3-one Keep a solution of 1.0 g. of dl-l 3,8-ethyl-3,3-ethylene-dioxy-17a-ethynyl-l7B-hydroxyl-l0,B-methylgon-5-ene in 30 ml. oftetrahydrofuran and 6 ml. of 3M perchloric acid at room temperature for2 hours. Basify the solution with 5% potassium bicarbonate concentrateunder vacuum and add water. Extract the mixture with chloroform, washthe extract with water, dry and evaporate. Chromatograph the residue onneutral alumina (Act. 3), elute with 1:19 ether-benzene and crystallizefrom acetone-hexane to obtain 0.31 g. of the title product, mp.205-207", Mil; 3.03, 3.08, 6.05, 6.22 ,u, x1273," 240 mp. (16,000), NMR:1.02 (triplet), 1.18, 2.27, 2.58, 5.57 p.p.m.

Analysisfor C,,H,O,:

Calculated C, 8093,11, 9.26%. Found. C, 80.94; H, 9.11%.

EXAMPLE l9 dl- 1 3B, 17B-Diethyl- 17B-hydroxylOB-methylgon-4-en-3-oncAdd a solutionof 1.2 g. of dl-l3B-ethyl-3,3-ethylene-dioxyl7a-ethynyl-l7B-hydroxy-lQB-methylgon-S-enein 50 ml. of ethyl acetate and 25 ml. of benzene to 0.6 g. of 2%palladium oxide-strontium carbonate catalyst prehydrogenated in 20 ml.of ethyl acetate and 20 ml. of benzene and hydrogenate at roomtemperature and atmospheric pressure. After 2% hours and an uptake of2.2 moles of hydrogen, filter the mixture and evaporate the filtrate toobtain 1.0 g. of oily dl-l3B,17adiethyl-3,3-ethylenedioxy-17B-hydroxy-lOfi-methylgon-S- ene.

Keep a solution of the above 1.0 g. of l7a-ethyl-3-ketal compound in 40ml. of tetrahydrofuran and 9 ml. of 3M perchloric acid at roomtemperature for 2 hours. Basify the solution with 5% potassiumbicarbonate, concentrate under vacuum and add water. Extract the mixturewith chloroform, wash the extract with water, dry and evaporate.Chromatograph the residue on neutral alumina (Act. 3), elute withbenzene and crystallize from acetone-hexane to obtain the title product(0.47 g.), m.p. 132133, Xfif; 2.95, 6.03, 6.18 x233, 241 m (16,000).NMR:1.20, 5.74 p.p.m.

Analysis for C H O Calculated C, 79.95; H, 10.37%. Foundc,79.e7;n,10.14%.

EXAMPLE 20 17B-Acetoxy-l3B-ethyl-3,3-ethylenedioxy-17a-ethynyl-10B-methylgon-5-ene Reflux 13B-ethyl-3,3-ethylenedioxy-17a-ethynyl-17B-hydroxy-10B-methylgon-5-ene (3 g.) with acetic anhydride (48 ml.)-acetylchloride (24 ml.)-pyridine (2.4 ml.) for 2 hours. Evaporate the mixtureto dryness under reduced pressure and partition the residue betweenbenzene-ether and water. Wash, dry and evaporate the organic layer toobtain the title product.

EXAMPLE 21 l7a-Acetyl-l7B-acetoxy-13/3-ethy1-3,3-ethylendioxylOB-methylgon-S-eneStir Dowex 50 ion exchange resin (400 ml.; acid form) for 30 minuteswith water (1.6 l.)-concentrated sulfuric acid (43 ml.). Decant off theliquid, wash the resin with water until free of sulfate ion, then add itto mercuric acetate (5 g.) in water (1.66 1.). Stir the mixture for 10minutes, pour off the liquid and wash the residue with water until freeof mercuric ion. Reflux an aliquot of this resin (200 ml.) withl7B-aeetoxy-l3 B-ethyl-3,S-ethylenedioxy-17a-ethynyl-IOB-methylgon-Sene(10 g.) in ethanol (300 ml.) for 6 hours. Filter the cooled mixture,dilute the filtrate with methylene dichloride (2.5 l.) and wash theresulting solution with water and evaporate it under reduced pressure.If the residue shows appreciable infrared absorption in the 6.0 1.region, reflux it for 5 hours in benzene (500 ml.)-ethylene glycol (50ml.) containing toluene p-sullonic acid (1 g.) using a Dean-Stark refluxhead for continual removal of water. Wash the cooled mixture with water,dry, and evaporate to dryness under reduced pressure. Chromatograph thisproduct or that obtained directly from the initial hydration reaction ondeactivate alumina eluting with benzene and mixtures of benzene andether to obtain the title product.

EXAMPLE 22 l3fi-Ethyl-3,3-ethylenedioxy-173-1-hydroxyethyl-IOB-methylgomS-ene Add l7u-acetyll 7fi-acet0xyl3B-ethyl-3,3-ethylcnedioxy- IOB-methylgon-S-ene (2.4 g.) intetrahydrofuran (100 ml.) to a stirred solution of lithium (1 g.) inliquid ammonia (100 ml.). After 30 minutes add methanol (80 ml.)followed by lithium (0.5 g.) in small pieces with further stirring.After a further 10 minutes add water, and extract the mixture withether. Evaporate the washed and dried ethereal solution to obtain thetitle product.

EXAMPLE 23 l7B-Acetyl-l 3B-ethyl-3,3-ethylenedioxy-1OB-methylgon-S- eneTo pyridine ml.) at 10-] 5 add chromium trioxide (8.82 g.) over 10minutes with stirring and after a further 15 minutes addl3B-ethyl-3,3-ethylenedioxy-175-1-hydroxyethyl-l0/3- methylgon-S-ene(9.7 g.) in pyridine ml.) with stirring. Allow the reaction mixture towarm to 25 and after stirring for a further 3 hours pour into ice water(1 l. and extract with ether. Evaporate the washed and dried extractsremoving the last traces of pyridine with azeotropic distillation withtoluene to obtain the title product.

EXAMPLE 24 l7B-Acetyle-13 B-ethyll 0B-methylgon-4-en-3-one.

Keep l7B-acetyle-l 3B-ethyl-3,3-ethylenedioxy-1OB-methylgon-5-ene (l g.)for 1% hours at 25 in acetone 100 ml.) containing p-toluenesulfonic acidmonohydrate mg.). Add aqueous sodium bicarbonate solution, extract theproduct with ether and purify it by chromatography on deactivatedalumina. Elute with mixtures of hexane-benzene, pure benzene, andmixtures of benzene-ether to obtain the title product.

EXAMPLE 25 l7B-2'-Acetoxyacetal- 1 3B-ethyll OB-methylgon-4-en-3-oneStir l7/3-acetyl-13B-ethyl-10/3methylgon-4-en-3-one (3 .91 g.) for 4hours at room temperature with lead tetraacetate (6.52 g.) in benzeneml.)-methanol (10 ml.) containing boron trifluoride-ether complex (25ml.). lsolate the product with chloroform and purify by chromatographyon deactivated alumina. Elute with mixtures of pentane-benzenc and purebenzene to obtain the title product.

EXAMPLE 26 l7B-2-Acetoxyacetyl-l3B-ethyl-3,3-ethylenedioxylOB-methylgon-S-ene Stirl7B-acetyl-13B-ethyl-3,3-ethylenedioxy-1OB-methylgon-5-ene (3.53 g.) for4 hours at room temperature with lead tetra-acetate (6.52 g.) in benzene(190 ml.)-methanol (10 ml.) containing boron trifluoride-ether complex(25 ml.). 150- late the product with chloroform and purify bychromatography on alumina. Elute with mixtures of pentane-benzene andpure benzene to obtain the title product.

EXAMPLE 27 l7B2-Acetoxyacetyl-l 3/3-ethyl l ()dmethylgont-en-3-one Keepl7fl-2'-acetoxyacetyl-l 3B-ethyl-3.3-ethylenedioxylO/3-methylgon-5-ene(2 g.) for 2 hours at room temperature in acetone (100 ml.) containingp-toluenesulfonie acid monohydrate (150 mg). Add sodium bicarbonatesolution, extract the product with ether and ehromatograph it ondeactivated alumina. Elute with mixtures of hexane-benzene and purebenzene to obtain the title product.

EXAMPLE 28 13B, l7-Diethyl-3,3-ethylenedioxy-lOB-methylgon-SJ7(20)-diene Add 20 mls. of phosphorous oxychloride dropwisc over 2 hours to astirring solution of 10 g. of l3l3,l7a-dicthyl-3,3-ethylenedioxy-l7/3-hydroxy-IOB-methylgon-S-ene in 50 ml. of pyridine andreflux the mixture for 2 hours. Pour the cooled reaction mixture intoice water, extract with ether, wash the extract with water, dry andevaporate. Chromatograph the residue on deactivated alumina and elutewith hexanebenzene mixtures to obtain the title product.

EXAMPLE 29 135-1 7- -Diethyl-lB-methylgon-4, l 7(20)-dien-3-one- Keep asolution of 2.0 g. of l3B,l7-diethyl-3,3-ethylenedioxy-l0/3-methylgon-5,l7(20)-diene and 0.3 g. ofptoluenesulfonic acid in 200 ml. of acetone for 2 hours at Add aqueoussodium bicarbonate solution, extract the product with ether and purifyit by chromatography on deactivated alumina. Elute with mixtures ofhexane-benzene, pure benzene and mixtures of benzene-ether to obtain thetitle. product.

EXAMPLE l 7/3-Acetyll 3B-ethyll 7ahydroxyl 0B-methylgon-4-en-3- oneTreat an ice-cold solution'of 3.8 g. of 13/3, l7-diethyl-l0/3-methylgon-4,l7(20)-dien-3-one in 200 ml. of t-butyl alcohol containing9.3 ml. of pyridine and and L9 ml. of water with 3.8 g. ofN-methylmorpholine oxide, 8.0 g. of phenyl iodosoacetate and mg. ofosmium tetroxide. Stir the slurry ml. of water and stir the mixture for15 minutes. Filter, concentrate the filtrate, dilute with water andextract with"- chloroform. Wash the extract with water, dry, andevaporate. Chromatograph the residue on deactivated alumina and elute.with benzene-ether mixtures to obtain the title product.

EXAMPLE 3| l7a-Acetoxy, l7B-acetyl -l 3B-ethyl-lOB-methylgon-4-cn-3' oneEXAMPLE 32 l BB-Ethyll 7B'hydroxy- 10B-methylgon-4-en-3-on-l7aylpropynoic acid Add methylmagnesium bromide in tetrahydrofuran (6 ml;of 3M) with stirring to a refluxing solution of l3B-ethyl-3,3-ethylenedoxy-l7a-ethynyl-lOfi-methyl-l7B-hydroxygon-5- ene (0.8 g.) intetrahydrofuran (5 ml., previously distilledv from methylmagnesiumbromide). Reflux with stirring for 24: hr. under carbon dioxidemaintained at a pressure slightly greater than atmospheric. Add thecooled mixture to an excess of ice cold 0.4 N sulfuric acid and removemost ofthe solvents under reduced pressure. Extract the residue witheither and evaporate the washed and dried extracts. Chromatograph: theresidue on silica gel elute with benzene, benzene-ethylacetate mixtures,and pure ethyl acetate to obtain the title: product.

EXAMPLE 33 3(13fi-Ethyl-l7B-hydroxy-l0B-methylgon-4-en-3-on-l7a-yl)propionic acid lactone Shake a solution of 13B-ethyl-l7B-hydroxy-lOB-methylgom 4-en-3-on-a-yl acid (0.37 g.) in methanol (60ml.) containing 2% palladised strontium carbonate (0.1 g.;prehydrogenated in situ) until 2 milliequivalents of hydrogen (ca. ml.)are taken up. Add celite, filter the suspension and evaporate thefiltrate to obtain the title product.

.25 at 0 for 2 days, add a solution of 1.5 g. of sodium sulfite in 100EXAMPLE 34 propionic acid lactone Reflux 3-( l 3B-ethyl-l7B-hydroxyl0B-methylgon-4-en-3- on-l7ayl) propionic acid lactone (0.5g.) for 2 hr. in acetic anhydride (9 ml;)-acetyl chloride (3.5ml.)-pyridine (0.35 ml.). Evaporate the solution under reduced pressureto obtain the crude 3-(3-acetoxy-l3fi-ethyl-l7/3-hydroxy-l0B-methylgona-3,5-dien-l7a-yl)propionic acid lactone. Add N- bromosuccinimide (0.275 g.) portionwisewith stirring to the foregoing acctoxylactone (0.55 g.) in acetone (47.3ml.)- water 15 ml.) at 0 containing pyridine (0.32 ml.), acetic acid(1.5 ml.) and sodium acetate (1.5 g.). Stir the mixture for 2 hr., addit to brine and extract with ether. Evaporate most of V the ether at [5under reduced pressure, then add calcium carbonate (1.65 g.) anddimethylformamidc (38.5 .ml.). Evaporate the remaining ether and refluxthe mixture fora further 2 hr. Filter the cooled mixture, wash thefiltered solids with ether, combine the filtrate and washings andevaporate the washed and dried organic solution. Chromatograph theresidue on acid-washed alumina, eluting with benzene and benzene-ethermixtures to obtain the title product.

EXAMPLE 35 3(7a-Acetylthiol 3B-ethyl-l 7/3-hydroxyl 0B-methylgon-4 en-3on-l 7aon-l7a-yl)propionic acid lactone Reflux -3-(l 3fl-ethyl-l7B-hydroxyl 0B-mcthylgona-4,6- dien-l7u-yl) propionic acid lactone(0.225 g.) in thioacetic acid (1 ml.) for 2 hr. Remove the excess acidunder reduced pressure and'chromatograph the residue on'silica gel,eluting with benzene and benzene-ether mixtures to obtain the titleproduct.

EXAMPLE 36 dll 3B-Ethyll 0B-methylgon-4-en-3 l 7-dione Keep a solutionof L0 g. of dl-l 3B-ethyl-3,3-ethylcnedioxy- 10B-methylgon-5-en-17-onein 30 ml. of tetrahydrofuran and 6 ml. of 3M perchloric acid at roomtemperature for 2 hours. Basify the solution with-5% potassium.bicarbonate, concentrate under vacuumand add water. Extract withchloroform wash with water, dry and evaporate. Chromatograph the residueon deactivated alumina and elute with benzene-ether mixtures to obtainthe title product.

The subject matter which theapplicants regard as their invention isparticularly pointed out and distinctly claimed as follows:

l. A process for preparing a l3-alkyl-l0-methylgon-4-en-3- onecomprising:

a. converting alO-methyl-l3-alkylgonan-4-onc to its 3- hydroxymethylenederivative by reacting said gonan-4- one with'an alkyl formate in thepresence of an alkali metal alcoholate,

b. converting the 3-hydroxymethylene derivative to the 3- oximinoderivative by reaction with an alkali metal nitrite,

c. hydrolyzing the oximino group in the presence of an acid to obtainthe 4-hydroxy-4-en-3-one derivative, mesylating the 4-hydroxy group inthe presence of an organic base,

e. catalyticallyhydrogenating the unsaturation at the 4-position withhydrogen in the presence of a catalyst,

f. eliminating the 4-mesyloxy group in the presence of an alkali metalsalt to form the 4-en-3-one conjugated system.

2. The process of claim 1, wherein the l3-alkyl group is methyl.

3. The process of claim 2, wherein the l3-alkyl group is 7. A compoundhaving the structure ethyl. R

4v A compound having the structure R O l l l O- V ()S 02013.:

6 wherein R is a polycarbonalkyl group containing from 2 to wherein R isa polycarbonalkyl group containing from 2 to about abo t l5 16 carbonatoms,

l6 a b atoms, d R is hydrogen or lower carboxylic acid acyl. R ishydrogen or lower carboxylic acid acyl. A Compolmd ofclalm 7 wherem R y5. A compound of claim 4 wherein R is ethyl. B- Y B- Y yfiy 6.l3B-Ethyl-4, 1 7B-dihydroxy-10/3-methylgon-4-en-3-one, acetate,4-mfilhancsulfonalel7-acetate. 20

2. The process of claim 1, wherein the 13-alkyl group is methyl.
 3. Theprocess of claim 2, wherein the 13-alkyl group is ethyl.
 4. A compoundhaving the structure
 5. A compound of claim 4 wherein R is ethyl.
 6. 13Beta -Ethyl-4,17 Beta -dihydroxy-10 Beta -methylgon-4-en-3-one,17-acetate.
 7. A compound having the structure
 8. A compound of claim 7wherein R is ethyl.
 9. 13 Beta -Ethyl-4,17 Beta -dihydroxy-10 Beta-methyl-4-en-3-one, 17-acetate, 4-methanesulfonate.